The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal in mice

Stewart, Mark A.; Albert, Mareike; Sroczyńska, Patrycja; Cruickshank, V. Adam; Guo, Yao; Rossi, Derrick J.; Helin, Kristian; Enver, Tariq

doi:10.1182/blood-2014-08-596734

Cited by 40 publications

(36 citation statements)

References 18 publications

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“…9,10 The function of the other JARID enzymes in the cardiovascular system has not been studied. In this study, we found the enzyme JARID1B, which has been implicated in cell fate decision, cancer progression, and stem cell self-renewal, 5,[11][12][13] to be highly expressed in ECs. By its JmjC domain, JARID1B catalyzes the demethylation of H3K4me2 and H3K4me3.…”

mentioning

confidence: 89%

“…14,15 Through this function, JARID1B is involved in the repression of transcription during embryonic development and in embryonic and hematopoietic stem cells. 5,8,11,12,16,17 Therefore, genetic deletion of JARID1B impairs mouse and porcine embryonic development. [18][19][20][21] Considering its effect on gene regulation, we hypothesized that JARID1B affects the expression of endothelial genes and examined the consequences on angiogenesis in human umbilical vein ECs (HUVECs), tamoxifen-inducible conditional, and in the endothelial-specific Jarid1b knockout mouse.…”

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confidence: 99%

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Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

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Hitzel

et al. 2015

ATVB

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Objective-Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. Approach and Results-To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. Conclusions-JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylasedependent manner.

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confidence: 89%

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confidence: 99%

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Fork

Hitzel

et al. 2015

ATVB

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“…4, Table S5C), and a group of multi-functional transcription factors, such as the activators/repressors SP1 and SP2 and development and oncogenesis regulators SRF, SIX5, JunD, c-Myc. JARID1A, an H3K4 demethylase required for haematopoietic stem cell self-renewal, 43,44 showed marginal enrichment in some, but an overall strong depletion, in the majority of aDMRs and aGENs. These results further strengthen the connection of aDMRs and aGENs with the binding of Polycomb repressive complex 2 in the absence of activating transcription factors.…”

Section: Rna Polymerase II and Other Transcription Initiation Factorsmentioning

confidence: 99%

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

Dozmorov

2015

Epigenetics

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Although age-associated gene expression and methylation changes have been reported throughout the literature, the unifying epigenomic principles of aging remain poorly understood. Recent explosion in availability and resolution of functional/regulatory genome annotation data (epigenomic data), such as that provided by the ENCODE and Roadmap Epigenomics projects, provides an opportunity for the identification of epigenomic mechanisms potentially altered by age-associated differentially methylated regions (aDMRs) and regulatory signatures in the promoters of ageassociated genes (aGENs). In this study we found that aDMRs and aGENs identified in multiple independent studies share a common Polycomb Repressive Complex 2 signature marked by EZH2, SUZ12, CTCF binding sites, repressive H3K27me3, and activating H3K4me1 histone modification marks, and a "poised promoter" chromatin state. This signature is depleted in RNA Polymerase II-associated transcription factor binding sites, activating H3K79me2, H3K36me3, H3K27ac marks, and an "active promoter" chromatin state. The PRC2 signature was shown to be generally stable across cell types. When considering the directionality of methylation changes, we found the PRC2 signature to be associated with aDMRs hypermethylated with age, while hypomethylated aDMRs were associated with enhancers. In contrast, aGENs were associated with the PRC2 signature independently of the directionality of gene expression changes. In this study we demonstrate that the PRC2 signature is the common epigenomic context of genomic regions associated with hypermethylation and gene expression changes in aging.

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“…A search of the Oncomine database (59,60) showed that JARID1B is up-regulated in multiple types of leukemia (46). JARID1B is important for hematopoietic stem cell renewal (47,48) and is overex- pressed in acute myeloid leukemia. Our data demonstrated a strong increase in expression of JARID1B in B-ALL as compared with normal bone marrow.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular inhibition of JARID1B using siRNA has shown that JARID1B is important for hematopoietic stem cell renewal (47,48). Here, we tested the effect of pharmacological inhibition of JARID1B on the proliferation of leukemia cells.…”

Section: Inhibition Of Ck2 Restores Ikaros-mediated Repression Of Jarmentioning

confidence: 99%

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Wang

Song

Ding

et al. 2016

Journal of Biological Chemistry

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Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumorsuppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.IKZF1 encodes the Ikaros DNA-binding zinc finger protein (1-4). Ikaros is essential for normal hematopoiesis and acts as a tumor suppressor (5, 6). In humans, deletion of a single Ikaros allele is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL) 3 that is characterized by resistance to chemotherapy and poor prognosis (7-9). Alterations in the Ikaros have also been associated with T cell ALL (10, 11) and myeloid leukemias (12-16). Ikaros regulates transcription of its target genes via chromatin remodeling (9). Ikaros has been shown to directly bind histone deacetylases HDAC1 and HDAC2 and to associate with the chromatin remodeling complex NuRD through interaction with the Mi-2 protein (9, 17).Ikaros is hypothesized to recruit chromatin remodeling complexes to the regulatory elements of its target genes, resulting in chromatin modifications (primarily histone deacetylation) and transcriptional repression or activation of its target genes (18 -20). Mechanisms of Ikaros-mediated repression that are independent of histone deacetylase have also been described (18, 3 The abbreviations used are: B-ALL, B-cell precursor acute lymphoblastic leukemia; CK2, casein kinase 2; TSS, transcriptional start site; ALL, acute lymphoblastic leukemia; TBB, 4,5,6,7-tetrabromobenzotriazole; IK haploid , Ikaros haploinsufficiency; Ikaros-CTS, C terminus o...

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The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal in mice

Abstract: Key Points Jarid1b is not required for steady-state hematopoiesis. Jarid1b is required for HSC self-renewal.

Cited by 40 publications

References 18 publications

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

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